WO2003022433A2 - Compose macrocyclique derivatise pour liaison covalente a un substrat, procede de formation correspondant et utilisation - Google Patents

Compose macrocyclique derivatise pour liaison covalente a un substrat, procede de formation correspondant et utilisation Download PDF

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WO2003022433A2
WO2003022433A2 PCT/US2002/028446 US0228446W WO03022433A2 WO 2003022433 A2 WO2003022433 A2 WO 2003022433A2 US 0228446 W US0228446 W US 0228446W WO 03022433 A2 WO03022433 A2 WO 03022433A2
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group
derivatized
macrocycle
linker
substituted
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PCT/US2002/028446
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WO2003022433A3 (fr
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Andrei V. Bordunov
L. Andy Woodruff
Christopher A. Pohl
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Dionex Corporation
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Priority to EP02766250A priority patent/EP1423394A2/fr
Priority to AU2002329993A priority patent/AU2002329993A1/en
Publication of WO2003022433A2 publication Critical patent/WO2003022433A2/fr
Publication of WO2003022433A3 publication Critical patent/WO2003022433A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/08—Bridged systems

Definitions

  • the present invention relates to a derivatized macrocycle compound capable of covalent bonding to a support substrate for uses such as high performance ion exchange chromatography.
  • Macrocyclic compounds such as crown ethers, cryptands, spherands, cryptahemispherands, cavitands, calixarenes, resorcmorenes, cyclodextrines, porphyrines and others are well known. (Comprehensive Supramolecular Chemistry Vol. 1-10, Jean-Marie Lehn - Chairman of the Editorial Board, 1996 Elsevier Science Ltd.) Many of them are capable of forming stable complexes with ionic organic and inorganic molecules. Those properties make macrocyclic compounds candidates for various fields, for instance, catalysis, separations, sensors development and others. Cryptands (bicyclic macrocycles) have extremely high affinity to metal ions.
  • the cryptand metal ion complexes are more stable than those formed by monocyclic ligands such as crown ethers (Izatt, R.M., et al., Chemical Reviews 91:1721-2085 (1991)).
  • monocyclic ligands such as crown ethers
  • This high affinity of the cryptands to alkaline and alkaline earth metal ions in water makes them superior complexing agents for the processes where strong, fast and reversible metal ion binding is required. Examples of these processes include separation, preconcentration and detection of metal ions, analysis of radioactive isotopes, ion-exchange chromatography, phase-transfer catalysis, activation of anionic species and others.
  • Adding moieties with functionality to macrocyclic compounds permits binding of the derivatized macrocycles onto support substrates to provide surface functionalization.
  • Physical adsorption and covalent attachment are two common methods of binding.
  • Cryptand adsorbed polymers have been reported as stationary phases for ion exchange chromatography (Lamb, J.D., et al., J.
  • Macrocyclic compounds containing allylic functionalities are known from prior art (Krakowiak, K.E., et al., Journal of Hetercyclic Chemistry 27:1011-1014 (1990)). Some of them were further hydrosilylated and attached to silica solid supports (Bradshaw, J.S., et al., Pure & Appl. Chem. 61:1619-1624 (1989); Bradshaw, J.S., et al., Journal of Inclusion Phenomena and Molecular Recognition in Chemistry 7:127-136 (1989)). The synthesis of allyl containing [2.2.2] cryptand 1 has been reported (Babb, D.A., et al., Journal of Heterocyclic Chemistry 23:609-613 (1986)).
  • the methods for covalent attachment of the cryptands to polymeric substrates are based mostly on the interaction of active layer of a substrate, for example, benzyl chloride groups with hydroxyl or amino functionalized cryptand molecules (Montanari, F., et al., J Org. Chem., 47:1298-1302 (1982) ; Montanari, F., et al., British Polymer Journal, 16:212-218 (1984) and Montanari, F., et al, Tetrahedron Letters, No 52, 5055-5058 (1979)).
  • This interaction also involves the side process - formation of the quaternary centers from the tertiary nitrogens of the macrocycle (Montanari, F., et al., British Polymer Journal, 16:212-218 (1984)). Quaternisation causes extended decomposition of the macrocycle via Hofmann degradation reducing the capacity of the anion exchange stationary phase.
  • An amide group is another linker reported for a covalent functionalization of the substrates with cryptand molecules (Montanari, F., et al., British Polymer Journal, 16:212-218 (1984)). Amides do not withstand the extremely high pHs used in anion exchange chromatography. Moreover, most of the described synthetic routes for producing hydroxyl or amino functionalized cryptands, are not practical to satisfy the requirements of industrial scale production.
  • M is a molecular framework monocyclic or polycyclic macrocycle moiety containing at least 12 atoms in each cycle
  • L is a substituted or unsubstituted carbon chain linker covalently bound to M including at least one carbon atom in a structure selected from the group consisting of an aliphatic, aromatic or heterocyclic linker including heteroatoms substituted for hydrogen atoms on the linker;
  • R is a terminal functional moiety capable of covalent binding to a support substrate or of being converted into a functional moiety capable of covalent binding to a solid support substrate;
  • X and Y are moieties selected from the group consisting of protons, aliphatic groups, aromatic groups, optionally including heteroatoms, substituted for hydrogen atoms in the moieties, selected from the group consisting of oxygen, nitrogen, sulfur, or phosphorus heteroatoms; and
  • S is sulfur
  • M is a cryptand
  • the foregoing derivatized macrocycle structure is prepared by reacting HSR under free radical activation conditions with the intermediate
  • the foregoing derivatized macrocycle compound is covalently bound to a support substrate Z to form the following structure:
  • Ri is the covalent linker between sulfur atom S and a support substrate Z.
  • Ri is formed by a conversion of R ( structure (1)) upon derivatization of Z.
  • Ri is a substituted or unsubstituted carbon chain linker including at least one carbon atom in a structure selected from the group consisting of an aliphatic, aromatic or heterocyclic linker including heteroatoms substituted for hydrogen atoms on the linker.
  • Ri can be a polymeric chain.
  • FIG. 1 is a schematic representation of a derivatized cryptand bound to a support substrate.
  • FIGS. 2 and 3 are chromatograms of the ion exchange composition of the present invention.
  • macrocyclic compounds are derivatized by the use of a sulfur-containing derivatizing agent to form a product which includes a terminal functional moiety R bound, directly or indirectly, through a sulfur atom S to the macrocyclic compound.
  • R is capable of covalent binding to a support substrate or of being converted into a form capable of covalent binding to such a substrate, h general, the derivatized macrocyclic compound has the following structure: (1)
  • M is a molecular framework monocyclic or polycyclic macrocycle moiety containing at least 12 atoms in each cycle;
  • L is a substituted or unsubstituted carbon chain linker covalently bound to M including at least one carbon atom in a structure selected from the group consisting of an aliphatic, aromatic or heterocyclic linker including heteroatoms substituted for hydrogen atoms on the linker;
  • R is a terminal functional moiety capable of covalent binding to a support substrate or of being converted into a functional moiety capable of covalent binding to a solid support substrate;
  • X and Y are moieties selected from the group consisting of protons, aliphatic groups, aromatic groups, optionally including heteroatoms, substituted for hydrogen atoms in the moieties, selected from the group consisting of oxygen, nitrogen, sulfur, or phosphorus heteroatoms; and
  • S is sulfur
  • Suitable macrocyclic compounds M are monocyclic, bicyclic, tricyclic or polycyclic molecular frameworks.
  • macrocyclic compounds include crown ethers, cryptands, spherands, cryptahemispherands, cavitands, calixarenes, resorcmorenes, cyclodextrines and porphyrines such as of the type described above.
  • the R group in structure (1) can be covalently bound in one or more steps to a support substrate Z to form the following structure: (3)
  • Ri is a covalent linker between S and Z. It can be a substituted or unsubstituted carbon chain including at least one carbon atom in a structure selected from the group consisting of an aliphatic, aromatic or heterocyclic linker including heteroatoms substituted for hydrogen atoms on the linker.
  • R t is illustrated to be directly bound to Z, it can be bound to an intermediate compound which is capable of covalent binding to Z, as shown in reactant scheme (5).
  • the -R ⁇ -Z linkage of structure (3) encompasses a direct and indirect bonding and does not exclude such an intermediate linkage .
  • Any support substrate Z can be used so long as M in structures (1) - (3) is capable of performing its desired function, e.g., to serve as an ion exchanger.
  • One form of structure (3) is a packed bed of particles of derivatized macrocycle compound covalently bound to substrate Z.
  • Suitable substrates include organic or inorganic materials such as cross-linked and uncross-linked polymers, resins, organic or inorganic monoliths, sol-gels, other forms of gels such as silica gels, inorganic supports such as zeolites, aluminum oxide, titanium dioxide, zirconium based supports, glasses, carbon black, activate carbon, carbon nanotubes, fibers, pyrolized materials, organic and inorganic crystals, liquid crystals, colloids, nanoparticles, organic and inorganic gels, latexes, foams, membranes and films.
  • organic or inorganic materials such as cross-linked and uncross-linked polymers, resins, organic or inorganic monoliths, sol-gels, other forms of gels such as silica gels, inorganic supports such as zeolites, aluminum oxide, titanium dioxide, zirconium based supports, glasses, carbon black, activate carbon, carbon nanotubes, fibers, pyrolized materials, organic and inorganic crystals, liquid crystals,
  • Z may be in the form of monolayers such as surfaces of chips, silicon wafers, the walls of capillaries used for gas, liquid, capillary and ion exchange chromatography, capillary electrophoresis, separation, extraction, solid phase extraction, filtration, purification, transport, complexation, molecular and ion recognition, concentration, sensing an analysis of organic and inorganic molecules and ions and also for catalysis, phase transfer catalysis, solid phase synthesis or for other applications.
  • monolayers such as surfaces of chips, silicon wafers, the walls of capillaries used for gas, liquid, capillary and ion exchange chromatography, capillary electrophoresis, separation, extraction, solid phase extraction, filtration, purification, transport, complexation, molecular and ion recognition, concentration, sensing an analysis of organic and inorganic molecules and ions and also for catalysis, phase transfer catalysis, solid phase synthesis or for other applications.
  • One particularly useful macrocycle comprises a cryptand bound to a support substrate such as resin copolymer particles in a flow-through ion exchange bed, e.g., using the cryptand functional bed for anion exchange chromatography.
  • a macrocyclic compound M is derivatized to include a pendant reactive moiety such as an allylic group by well known methods as described above.
  • M is defined to include such reactive moieties which are capable of bonding to HSR as described below.
  • the HSR reagent is covalently bound to M to form an intermediate product of the type shown in structure (1) in which the R group is covalently bound to the macrocycle indirectly through the sulfur atom S.
  • the R group can be in a functional form suitable for direct or indirect covalent attachment to the support substrate in a single or multiple steps.
  • Scheme (4) illustrates the derivatization of macrocyclic compound (2) with HSR under the conditions of free radical addition, hi a particular case compound (2) is the cryptand with the allylic pendant moiety.
  • S is connected to the macrocycle M through the intermediate linker L including at least one carbon atom.
  • L is disposed between M and an unsaturated carbon to carbon bond U which interconnects L and the terminal carbon atom bound to Y.
  • the purpose of linker L is to incorporate function U into the macrocycle M.
  • the unsaturation is preferably provided by the double bond, e.g., a terminal allyl group.
  • Linker L may be attached to M at any site that does not significantly affect the ability of the macrocycle to provide the desired function, e.g., to complex with an ion of interest. Thus, for a cryptand, the attachment would not significantly affect binding of the cation or its associated anion.
  • the backbone of the linker L is preferably from about 1 to about 20 atoms in length, preferably from 3 to 8 atoms in length.
  • the linker chain may be straight chained or branched and it may also include saturated or unsaturated carbon atoms for heteroatoms substituted for hydrogen atoms on the linker including oxygen, nitrogen, sulfur or phosphorus.
  • the linker group will contain from 1 to 3 heteroatoms.
  • the heteroatoms may be placed in the linker chain at positions where they will have no significant adverse affect on the ion separation characteristics of the composition.
  • the linker group L can be similar to the corresponding linker L in U.S. Patent No. 5,865,994, incorporated herein by reference.
  • R is in a form capable of direct covalent attachment to a support substrate without converting R to a form capable of covalent attachment.
  • the conversion of R such as protection/deprotection reactions might be necessary to keep R intact during the reaction (4).
  • Another reason for an optional protection/deprotection of R is to prevent the interference of group R with the course of reaction (4).
  • the example of the protection/deprotection of R is using a carboxylic acid in a form of ester protected R group in reaction (4) followed by its conversion ( deprotection) to carboxylic acid upon hydrolysis, prior to its attachment to a substrate.
  • the groups R suitable for a direct covalent attachments to a support substrate with the possible use of protection/deprotection include proton, amines, epoxides, aldehydes, ketones, alcohols, phenols, thiols, carboxylic acids, thiocarboxylic acids, amides and esters of carboxylic and thiocarboxylic acids, phosphoric and phosphonic acids, esters of sulfonic acids.
  • the first method is the conversion of R to a group capable of covalent binding to a substrate under non radical conditions to form structure (3).
  • the example of this approach can be a conversion of (1) where R is the alcohol moiety.
  • the alcohol group can be easily transformed into a tosyl or mesyl derivative which reacts with the deprotonated hydroxyl groups of a support substrate to form a covalent link Ri.
  • Functional groups that can be prepared by conversion of R for the further non radical covalent attachment to a substrate include amines, epoxides, aldehydes, ketones, alcohols, phenols, thiols, carboxylic acids, thiocarboxylic acids, amides and esters of carboxylic and thiocarboxylic acids, phosphoric and phosphonic acids, esters of sulfonic acids, acyl halides , alkyl and aryl halides and activated carboxylic acids.
  • the second method of indirect attachment of (1) to a support substrate is the conversion of group R into polymerizable moiety followed by its covalent binding to a substrate under free radical conditions.
  • the indirect attachment of the below specific reaction scheme (5) illustrates a two-step procedure in which ⁇ SR in the HSR reagent first is bonded through linker L to M. Then, in a second step, the bound R is reacted with another reagent to form a pendant group on R capable of covalent binding to a substrate via radical process.
  • the pendant group is an ethylenically unsaturated (vinyl) group which can be bound to the support substrate under free radical activation conditions.
  • an allyl derivative of [2.2.2] cryptand 1 is first formed by known chemistry as described above. Then, it is covalently bound to the HSR reagent (2-aminoethanethiol hydrochloride) through the allyl group to form a terminal amino group R, such as by free radical conditions such as the exposure to UV or other irradiation and/or by addition of peroxides, azo compounds, etc. , e.g., as illustrated in the review of Griesbaum, K., Angew. Chem. Internat. Edit. Vol.9, No.4, 273-287 (1970).
  • amino group R is converted to a function capable of binding to a substrate under free radical conditions e.g., a vinyl group.
  • a substrate under free radical conditions e.g., a vinyl group.
  • the first step of this conversion is the interaction of amino cryptand 2 with 4- vinylbenzaldehyde.
  • Schiff base is the intermediate product of this reaction (not shown on the scheme).
  • Schiff base is reacted in situ with NaBH 4 to give [2.2.2] cryptand 3 functionalized with polymerizable styryl moiety.
  • This approach allows ready conversion of macrocycles into functionalized molecules for their further covalent attachment or incorporation into or onto various substrates using free radical process such as grafting and coating.
  • An important feature of the present invention is the functionalization of macrocyclic molecules via radical addition of thiols ( schemes (4) and (5)). Advantages of this process include:
  • allyl cryptand 1 described in prior art is the superior method to build the macrocyclic framework of [2.2.2] cryptand having pendant function for further attachment.
  • the use of allyl group alleviates the need for protection/deprotection steps during the synthesis of the cryptands.
  • Most of the prior art examples of cryptand functionalization are based on protected intermediates with longer routes for their synthesis effecting the total outcome of the process.
  • the method developed on a base of the allyl precursor allows 100-200g scale production of the functionalized [2.2.2] cryptand. This is unusually large amount for all described methods of the cryptand synthesis. 2.
  • the methods for a conversion of allyl cryptand to more reactive functional molecules are limited.
  • Allylic cryptand 1 converted to a styrenic derivative 3 now can be efficiently grafted from the surface of the support providing novel high capacity anion exchange stationary phase. 4.
  • Chemical stability of the stationary phases used in ion exchange chromatography is of great importance.
  • the extreme pHs at which the ion exchange chromatography is performed impose considerable limitations on chemistry of the functional monomers and linkers connecting the ion exchange sites with the stationary phase.
  • the developed thiol addition method followed by grafting polymerization provides extremely stable anion exchange materials on a base of the cryptand functionalized resins.
  • These stationary phases can be operated at pH 1-14 at elevated temperatures. The ruggedness and reproducibility of these phases after subjecting them to such harsh conditions are superior to similar characteristics of the existing anion exchange materials.
  • the illustrated R group is NH which reacts to form styrenic [2.2.2] cryptand 3 in which the pendant vinyl group can form a covalent bond with a corresponding vinyl group on a copolymer resin support substrate under free radical conditions as illustrated in Example 3 and FIG. 1.
  • reaction schemes of the present invention is that individual multiple (e.g., 4 x 10 14 to 4 x 10 16 or more) strands of derivatized macrocycle compounds (e.g., cryptands) per square meter can be bound to each support particle and projecting therefrom as illustrated in FIG. 1.
  • This provides a substantial quantity of macrocycle compounds in a format which is readily accessible to the approach of both cationic and anionic species in an aqueous environment.
  • Prior art based on adsorbed macrocycle compounds provides very limited capacity due to the restriction that this species must be adsorbed as a monolayer on a hydrophobic surface.
  • the macrocycle compounds as a brush polymer extending into the aqueous solution surrounding each support particle, permits significantly better diffusion lcinetics than can be observed with adsorbed monolayer coatings of macrocycle compounds, while at the same time allowing for significantly higher capacity than is possible with an adsorbed monolayer coating. Furthermore, positioning the macrocycle compounds in the proximity of a hydrophobic surface compromises the chromatographic performance of materials based on adsorbed macrocycle compounds. Anionic hydrophobic compounds exhibit poor chromatographic efficiency when that retention site is located in the proximity of a hydrophobic surface unless organic solvent is added to the mobile phase.
  • Adsorbed macrocycle monolayer coatings of the prior art have been shown to be useful with macrocycle ion binding constants as low as 60.
  • macrocycles when constructed in the form of a covalently attached brush polymer coating failed to exhibit any useful ion binding characteristics in 100% aqueous environments.
  • applying a macrocycle as an adsorbed monolayer coating on a hydrophobic surface exposes the macrocycle to a substantially lower dielectric environment than the aqueous environment above the surface.
  • ion binding affinities of adsorbed monolayer coatings are substantially higher than the equivalent macrocycle in a 100% aqueous environment. Therefore, in order to produce a useful material in the highly desirable covalently bound brush polymer format, macrocycles must have higher ion binding constants in order to provide useful ion binding characteristics in 100% aqueous environments.
  • the vinyl moiety of the styrenic terminal group is readily attached under free radical conditions to polymeric substrate particles including terminal groups with ethylenic unsaturation as described in U.S. Patent 5,865,994 to form structure (3).
  • R is illustrated in the form of an amine converted to an unsaturated carbon-carbon bond, specifically a vinyl group.
  • Other terminal functional groups may be employed so long as they can be covalently bonded to a desired support substrate.
  • one useful effective composition is a derivatized macrocycle compound with sufficient ion exchange properties to separate charged molecules.
  • a particularly effective derivatized macrocycle compound of this type is a cryptand bound to a support substrate with anion exchange properties.
  • anion exchange properties is meant the capability of performing anion exchange chromatography.
  • Cryptands are particularly effective for anion separation because they provide ion binding characteristics sufficient for binding alkaline and alkaline earth metals under alkaline conditions and yet readily release these ions under acidic conditions, providing a convenient means of converting the cryptand from one alkali metal form to another.
  • One suitable support particle is a macroporous polymeric resin, e.g., vinylbenzene ethylene, cross-linked with divinylbenzene.
  • Suitable macroporous resins are illustrated in U.S. Patent 4,224,415.
  • a hydrophihc layer may be attached to Z which forms the covalent attachment with the derivatized macrocycle. This has the advantage of reducing hydrophobic interaction between hydrophobic analytes and the surface to which the macrocycles are covalently attached. This reduces the need for addition of solvent to the mobile phase which as noted above is undesirable. .
  • Suitable procedures are set forth in Examples 3 and 5.
  • This example describes a two-stage synthesis of a derivatized cryptand according to reaction scheme (5).
  • Solvent was evaporated under reduced pressure. The rest was dissolved in 100 ml of water. Lithium hydroxide was added to the aqueous solution to reach pH 11. The resulted solution was extracted three times with 100 ml of dichloromethane. Organic layer was extracted with 20% aqueous lithium hydroxide and water and dried over anhydrous sodium sulfate. After evaporation of the solvent, crude aminocryptand 2 was dissolved in 200 ml of methanol. To resulted solution, 12 g of 4-vinylbenzaldehyde in 40 ml of methanol was added over a 1 hour period. Reactants were refluxed in methanol for 6 hours in presence of 10 mg of 4-t-butylcatechol.
  • Methanol solution was filtered and cooled down to -5°C. 10 g of sodium borohydride was added slowly to resulted solution. The reaction was continued under reflux for 24 hours. Methanol was evaporated under reduced pressure and the residue was mixed with 80 ml of water; pH was brought to 1.5 with ice cold 30% methanesulfonic acid. The resulted solution was extracted three times with 150 ml of ether. Aqueous layer was brought to pH 11 with lithium hydroxide and extracted three times with 100 ml of dichloromethane. Combined organic fractions were extracted with water, dried over sodium sulfate and filtered. Solvent was evaporated under reduced pressure.
  • This example describes functionalizing the support substrate Z by depositing a hydrophihc layer for binding to a derivatized cryptand.
  • This example describes binding of the derivatized cryptand of Example 1 to the functionalized Z of Example 2.
  • Cryptand Monomer is Attached to Polymeric Particles Suitable for Use as a Packing
  • the resultant polymeric material from above was washed with acetone followed by methanol, water, and 1M potassium hydroxide.
  • the resin was then packed in an analytical column using standard methods and apparatus at 6000 psi for 15 minutes. This polymeric column is suitable for chromatographic separations of anionic species.
  • the derivatized cryptand of Example 1 is bound to the macroporous resin starting material of Example 2 (without forming the hydrophilic layer).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Solid-Sorbent Or Filter-Aiding Compositions (AREA)
  • Addition Polymer Or Copolymer, Post-Treatments, Or Chemical Modifications (AREA)
  • Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
  • Medicinal Preparation (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)

Abstract

L'invention concerne un composé macrocyclique dérivatisé de formule (1) dans laquelle M représente une entité de macrocycle, à structure moléculaire monocyclique ou polycyclique, L représente un élément de liaison à chaîne carbonée, substitué ou non substitué, lié à M par covalence, R représente un groupe fonctionnel terminal pouvant se lier par covalence à un substrat support Z ou pouvant être converti en groupe fonctionnel capable de liaison covalente avec un substrat support Z, notamment un grain de résine, X et Y représentent des groupes sélectionnés parmi le groupe constitué par des protons, des groupes aliphatiques, des groupes aromatiques, contenant éventuellement des hétéroatomes, et S représente un atome de soufre. Dans une réalisation préférée, M représente un cryptand.
PCT/US2002/028446 2001-09-07 2002-09-05 Compose macrocyclique derivatise pour liaison covalente a un substrat, procede de formation correspondant et utilisation WO2003022433A2 (fr)

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JP2003526553A JP2005501920A (ja) 2001-09-07 2002-09-05 基体に共有結合させるための誘導化大環状化合物、並びにその調製方法および使用
EP02766250A EP1423394A2 (fr) 2001-09-07 2002-09-05 Compose macrocyclique derivatise pour liaison covalente a un substrat, procede de formation correspondant et utilisation
AU2002329993A AU2002329993A1 (en) 2001-09-07 2002-09-05 A derivatized macrocycle compound for covalent bonding to a substrate and method of forming and use

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EP2745904A1 (fr) 2012-12-21 2014-06-25 Dionex Corporation Supports multimodaux d'échange de cation/d'échange d'anions/HILIC
US9169331B2 (en) 2012-12-21 2015-10-27 Dionex Corporation Separation of glycans by mixed-mode liquid chromatography
US9310344B2 (en) 2013-06-14 2016-04-12 Dionex Corporation HILIC/anion-exchange/cation-exchange multimodal media
US9314712B2 (en) 2008-05-09 2016-04-19 Dionex Corporation Functionalized substrates with ion-exchange properties

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US11740163B2 (en) 2011-02-14 2023-08-29 Dionex Corporation Nanometer size chemical modified materials and uses
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JP2005501920A (ja) 2005-01-20

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